Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000221478 | SCV000273726 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-03-06 | criteria provided, single submitter | clinical testing | The p.H193Y variant (also known as c.577C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 577. The histidine at codon 193 is replaced by tyrosine, an amino acid with some similar properties. <span style="background-color:initial">This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9<span style="background-color:initial">). Additional studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). <span style="background-color:initial">It has been reported in the database as both a germline mutation in a family with classic Li-Fraumeni Syndrome (LFS), and a somatic mutation in numerous tumors (IARC TP53 database). Another variant at this same amino acid position, p.H193R, has been identified in a patient with LFS, and shown to be severely deficient in transcriptional activation in yeast based assays (Frebourg et al. Am. J. Hum. Genet. 1995 Mar;56(3):608-15; Monti et al. <span style="background-color:initial">Mol. Cancer Res. 2011 Mar;9(3):271-9<span style="background-color:initial">).<span style="background-color:initial"> <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Gene |
RCV000412758 | SCV000491082 | likely pathogenic | not provided | 2016-08-01 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.577C>T at the cDNA level, p.His193Tyr (H193Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in many neoplasm types according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). A study by Shiraishi et al (2004) also showed absent transactivation activity at 37 degrees Celsius, while Soubeyran et al. (2011) showed nonfunctional transactivation using a functional analysis of separated alleles in yeast (FASAY) test. TP53 His193Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 His193Tyr occurs at a position that is conserved across species and is located in DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 His193Tyr to be a likely pathogenic variant. |
Invitae | RCV000809571 | SCV000949726 | likely pathogenic | Li-Fraumeni syndrome | 2018-12-26 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with tyrosine at codon 193 of the TP53 protein (p.His193Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family with Li-Fraumeni syndrome (PMID: 27328919). ClinVar contains an entry for this variant (Variation ID: 230256). This variant has been reported to affect TP53 protein function (PMID: 21514416, 14559903, 12826609). This variant disrupts the p.His193 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 7887414, 22265402, 25945745, 28724667, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Database of Curated Mutations |
RCV000418749 | SCV000508486 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429902 | SCV000508487 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440111 | SCV000508488 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419839 | SCV000508489 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430089 | SCV000508490 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441207 | SCV000508491 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423524 | SCV000508492 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434647 | SCV000508493 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441502 | SCV000508494 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421204 | SCV000508495 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431464 | SCV000508496 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445008 | SCV000508497 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424900 | SCV000508498 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432551 | SCV000508499 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444740 | SCV000508500 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425998 | SCV000508501 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436284 | SCV000508502 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419469 | SCV000508503 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426264 | SCV000508504 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437380 | SCV000508505 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only |